Abstract
Depression is a devastating illness with a lifetime prevalence of up to 20%. The neurotransmitter serotonin or 5-hydroxytryptamine (5-HT) is involved in the pathophysiology of depression and in the effects of antidepressant treatments. However, molecular alterations that underlie the pathology or treatment of depression are still poorly understood. The TREK-1 protein is a background K+ channel regulated by various neurotransmitters including 5-HT. In mice, the deletion of its gene (Kcnk2, also called TREK-1) led to animals with an increased efficacy of 5-HT neurotransmission and a resistance to depression in five different models and a substantially reduced elevation of corticosterone levels under stress. TREK-1–deficient (Kcnk2−/−) mice showed behavior similar to that of naive animals treated with classical antidepressants such as fluoxetine. Our results indicate that alterations in the functioning, regulation or both of the TREK-1 channel may alter mood, and that this particular K+ channel may be a potential target for new antidepressants.
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Acknowledgements
This work was supported by the CNRS and the Institut Paul Hamel. G.L. received a Canadian Institute for Health Research/Wyeth Fellowship, X.-D.P. received a Québec Merit Fellowship, G.D. was a National Researcher of the Fonds de la Recherche en Santé du Québec and S.T. received a Deutsche Forschungsgemeinschaft Fellowship. We are very grateful to Y. Jacomet for the MRS analysis of brain fluoxetine concentrations, to F. Lesage (CNRS Unité Mixte de Recherche, UMR 6097) for the TREK-1 antibody and to J. Costentin for discussions, to C. Gandin and M. Jodar for their technical help and to Y. Benhamou and L. Martin for secretarial assistance.
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Contributions
C.H. behavioral experiments, localization studies, data analysis and writing. G.L. in vivo electrophysiology and data analysis. N.G. production of knockout mice. M.E.Y. behavioral experiments. S.T. in vitro electrophysiology of antidepressants. X.-D.P. in vivo electrophysiology. F.N. behavioral experiments. N.B. localization studies and data analysis. C.W. localization studies and statistics. M.B. localization studies and biochemical experiments. G.G. in vivo electrophysiology. J.-M.V. behavioral studies. G.D. in vivo electrophysiological experiments, data analysis and writing. M.L. overall organization of the research work between the different authors and different teams, and writing.
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Supplementary information
Supplementary Fig. 1
TREK-1 immunolocalization throughout the network of limbic, striatal and prefrontal cortical neuronal circuits. (PDF 1149 kb)
Supplementary Fig. 2
TRAAK expression in 5-HT neurons of the dorsal raphe nucleus. (PDF 1975 kb)
Supplementary Fig. 3
5-HT selective reuptake inhibitors (SSRIs) inhibit human TREK-1 but not TRAAK currents. (PDF 280 kb)
Supplementary Fig. 4
Mean whole-brain fluoxetine concentrations after acute and chronic fluoxetine treatment. (PDF 28 kb)
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Heurteaux, C., Lucas, G., Guy, N. et al. Deletion of the background potassium channel TREK-1 results in a depression-resistant phenotype. Nat Neurosci 9, 1134–1141 (2006). https://doi.org/10.1038/nn1749
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DOI: https://doi.org/10.1038/nn1749
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